Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
  • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms

Definitions

• This invention relates to a neuroleptic agent and more particularly to 3- ⁇ 3-[4-(4-fluorobenzoyl)piperidyl] ⁇ -2-methyl indole or an acid addition salt thereof prepared from a pharmaceutically acceptable acid.
• U.S. Patent No. 4,046,900 describes benzoyl- piperidyl alkylindoles generally and in particular 3- ⁇ 3-[4-fluorObenzoyl)PiPeridyl]propyl ⁇ -indole which exhibit tranquilizing properties.
• the compounds of the present invention exhibit neuroleptic or tranquilizing properties without exhibiting the degree of or propensity towards production of extrapyramidal side effects such as are exhibited by the prior art neuroleptic agents heretofore described.
• a compound of the invention 3- ⁇ 3-L4-(4-fluorobenzoyl)piperidyl]propyl ⁇ -2-methylindole conforms to the formula
• the acid addition salts thereof are prepared from pharmaceutically acceptable acids.
• Acids useful for preparing the acid addition salts of the invention include inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, as well as organic acids such as tartaric, citric, acetic, succinic, maleic, fumaric and oxalic acids.
• the compounds of the invention are useful as neuroleptic agents. This activity is demonstrated in a number of standard assays for neuroleptic activity, including prevention of amphetamine toxicity in aggregated mice (AAT).
• mice It is well documented that the aggregation of mice in small chambers greatly increases the toxicity (lethality) of amphetamine. The prevention of this amphetamine lethality by neuroleptic agents has also been verified by many investigators and is generally cited as another indication of neuroleptic activity.
• AAT aggregation enhanced amphetamine toxicity
• mice Sixty minutes after experimental compound administration the mice are dosed with d-amphetamine sulfate by subcutaneous injection (21 mg/kg). The d-amphetamine sulfate is dissolved in distilled water at a concentration of 2.1 mg/cm 3 and immediately after dosing, the mice of each treatment group are aggregated in "stick-cages" in groups of five (e.g. two groups of five for each treatment group).
• the "stick-cages” are 10 consecutive cages 10 cm x 10 cm x 10 cm wire mesh with ca. 0.6 cm holes. These cages are subsequently place in close-fitting, plastic-lined containers consisting of only the floor and 10 cm walls. This aids in the maintenance of elevated temperatures (27-29°C) which has been found to be an important parameter.
• the room temperatur should be from 21 to 22°C during the test but the chamber.temperature is constantly monitored so that it does not exceed 29°C, for at extreme temperatures (31-32°C) even known neuroleptic agents may not prevent amphetamine induced lethality.
• estamination of the ED 50 values and 95 % confidence limits for protection is this test are calculated by a Probit analysis of the data using the number dosed versus the number surviving.
• the compound of the subject invention either does not have or exhibits a very low propensity to extrapyrimidal side effects as compared to the next lowest homolog described above. This is a surprising and unexpected result since most neuroleptics exhibit extrapyramidal side effects and certainly one would expect such side effects for the compounds of the invention, especially when structurally related prior art compounds (next lower homolog) appear to exhibit a propensity toward such side effects.
• the propensity for extraphyramidal side effects can be determined by apomorphine sterotypy and apomorphine emesis tests. The tests are carried out in the manner described below.
• Groups of male Wistar rats (125-200 gms) are used and food and water are available ad libitum.
• Drugs are prepared using destilled water and, if insoluble, a suitable surfactant is added.
• the route of administration may be varied and the dosage volume is 10 ml/kg.
• a group size of six is used.
• the drug is administered one hour prior to apomorphine challenge and the animals are caged.
• the control group receives vehicle.
• Apomorphine HC1 is prepared at a concentration of 12.5 mg/10 ml in 1 % saline.
• Apomorphine HC1 is administered at a dose of 1.25 mg/kg, intravenously, with a dosage volume of 1 ml/kg.
• Agitation is defined as restless motion and its presence (1) or absence (0) is scored.
• Stereotypic activity is defined as sniffing, licking, or chewing behavior which occurs in a repetitive manner and is rated as follows:
• the scores for the two parameters are separately added and averagedfor each animal. Any animal with an averaged response of less than the control scores in either parameter is considered to show anti-apomorphine activity for that parameter.
• the percent effectiveness of a drug is determined to be the percent inhibition shown by the drug.
• a dose response is run in the same manner as a primary screen except that a group size of ten is used and the animals are dosed in a randomized manner.
• One group receives vehicle.
• ED 's for agitation and/or stereotypy are calculated by means probit analysis.
• Imhibition of apomorphine induced emesis in the dog is as follows.
• Adult beagle dogs of either sex are used in treatment groups of. 3 to 9 dogs per dose.
• the dogs are housed in individual cages where water is available ad libitum and feed is presented once a day.
• the dogs are given the test compound orally as a mixture with lactose in a gelatin capsule. They are then dosed with a standard 0.15 mg/kg dose of apomorphine hydrochloride subcutaneously at various intervals after administration of the test compound.
• the initial screen is usually a dose of 1 mg/kg orally of the test compound.
• the dogs are first observed for overt behavioral effects, e.g., pupillary response to light, changes in salivation, sedation, tremors, etc. After the administration of apomorphine, the dogs are observed for stereotype sniffing and gnawing, and the emetic response. Emesis is defined as wretching movements followed by an opening of mouth and either attempted or successful injection of stomach content.
• the dose is propgressively lowered to obtain a minimal effective dose (MED) and/or an ED 50 value.
• MED minimal effective dose
• a computerized probit-analysis is used to calculate the data for ED 50 values and 95 % confidence limits.
• Activity in both apomorphine stereotypy and apomorphine emesis tests is indicative of dopamine blocking activity in the striatum, an area of the brain which is believed to be involved in extrapyramidal side effects in neuroleptics.
• clozapine a well-known neuroleptic, exhibits a negative activity in apomorphine stereotypy inhibition in rats (agitation: negative at 50 mg/kg; stereotypy: negative at 50 mg/kg) and is inactive from 2 to 10 mg/kg (orally) in apomorphine induced emesis in the dog.
• Clinically, clozapine has been shown to have a low incidence of extrapyramidal activity.
• the compound of the invention 3-3-[4-fluorobenzoyl)piperidyl]-propyl ⁇ -2-methyl indole is inactive in the apomorphine stereotypy assay at a dose of 25 mg/kg (subcutaneously) and shows only marginal activity of 33 % inhibition in the apomorphine emesis test at a dose of 5 mg/kg orally.
• the prior art compound 3- ⁇ 3-[4-(4-fluorobenzoyl)-piperidyl/propyl ⁇ indole displays the likelihood of extrapyramidal while the compound of the invention 3- ⁇ 3-[4-fluorobenzoyl)-piperidyl/propyli -2-methyl indole tested at similar or higher doses does not.
• the compounds of the present invention may be administered to a patient by a convenient route such as orally, intramuscularly, intraveneously, subcutaneously or intraperitoneally.
• a convenient route such as orally, intramuscularly, intraveneously, subcutaneously or intraperitoneally.
• the preferred route of administration is oral, for example, with an inert diluent or with an edible carrier or in gelatin capsules or tablets.
• the active compounds of this invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum and the like. These preparations should contain at least 0.5 % of active compound, but may be varied depending upon the particular form and may conveniently be between 7 % to about 70 % by weight of the unit. The amount of active compound in such compositions is such that a suitable dosage will be obtained.
• Preferred compositions and preparations according to the present invention are prepared so that an oral dosage unit form contains between 1 and 200 milligrams of active compound.
• the tablets, pills, capsules, troches and the like may also contain the following ingredients: a binder such as gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, potato starch and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
• a binder such as gum tragacanth or gelatin
• an excipient such as starch or lactose, a disintegrating agent such as alginic acid, potato starch and the like
• a lubricant such as magnesium stearate
• a sweetening agent such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
• a liquid carrier such as a fatty oil.
• Other dosage unit forms
• tablets or pills may be coated with sugar, shellac, or both.
• a syrup may contain, in addition to the active compounds sucrose as a sweetening agent, and certain preservatives, dyes and colorings, and flavors. Materials used in preparing these various compositions must be pharmaceutically pure and non-toxic in the amounts utilized.
• the active compounds of the invention may be incorporated into a solution of suspension. These preparations should contain at least 0.1 % of active compound, but may be varied to be between 0.5 and about 30 % of the weight thereof. The amount of active compound in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 0.5 to 100 milligrams of active compound.
• the solutions or suspensions may also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
• a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents
• antibacterial agents such as benzyl alcohol antioxidants such as ascorbic acid or sodium bisulfite
• chelating agents such as ethylenediaminetetraacetic acid
• buffers such as acetates, citrates or phosphates and

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Neurosurgery (AREA)
• Biomedical Technology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Neurology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)

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• 1980
  • 1980-07-07 US US06/166,419 patent/US4327103A/en not_active Expired - Lifetime
• 1981
  • 1981-07-01 ES ES503592A patent/ES8203881A1/es not_active Expired
  • 1981-07-02 EP EP81105121A patent/EP0046179A1/de not_active Withdrawn
  • 1981-07-07 JP JP56106829A patent/JPS5746981A/ja active Pending

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